论文标题 / Glucose feeds the TCA cycle via circulating lactate
期刊 / Nature
发表时间 / 2017-10-18
数字识别码 / 10.1038/nature24057
Mammalian tissues are fuelled by circulating nutrients, including glucose, amino acids, and various intermediary metabolites. Under aerobic conditions, glucose is generally assumed to be burned fully by tissues via the tricarboxylic acid cycle (TCA cycle) to carbon dioxide. Alternatively, glucose can be catabolized anaerobically via glycolysis to lactate, which is itself also a potential nutrient for tissues and tumours. The quantitative relevance of circulating lactate or other metabolic intermediates as fuels remains unclear. Here we systematically examine the fluxes of circulating metabolites in mice, and find that lactate can be a primary source of carbon for the TCA cycle and thus of energy. Intravenous infusions of 13C-labelled nutrients reveal that, on a molar basis, the circulatory turnover flux of lactate is the highest of all metabolites and exceeds that of glucose by 1.1-fold in fed mice and 2.5-fold in fasting mice; lactate is made primarily from glucose but also from other sources. In both fed and fasted mice, 13C-lactate extensively labels TCA cycle intermediates in all tissues. Quantitative analysis reveals that during the fasted state, the contribution of glucose to tissue TCA metabolism is primarily indirect (via circulating lactate) in all tissues except the brain. In genetically engineered lung and pancreatic cancer tumours in fasted mice, the contribution of circulating lactate to TCA cycle intermediates exceeds that of glucose, with glutamine making a larger contribution than lactate in pancreatic cancer. Thus, glycolysis and the TCA cycle are uncoupled at the level of lactate, which is a primary circulating TCA substrate in most tissues and tumours.
（导读 严冰）此前认为在哺乳动物中葡萄糖在有氧条件下主要直接进入 TCA 循环生成 CO2，也可通过糖酵解代谢为乳酸来供给组织营养。本文报导，乳酸可作为 TCA 循环的主要碳来源与能量来源。通过给小鼠注射 13C 标记的营养物，发现乳酸的循环量是各种代谢物中最高的，在喂食和禁食小鼠体内，分别是葡萄糖的 1.1 倍和 2.5 倍；在禁食阶段，除了大脑外所有组织中葡萄糖都主要通过乳酸进入 TCA 循环；在经基因改造的肺与胰腺癌肿瘤内，TCA 循环也更多利用乳酸而非葡萄糖。